NLRP3 Inflammasome: A New Target for Prevention and Control of Osteoporosis?

Abstract

Osteoporosis is a systemic bone metabolism disease that often causes complications, such as fractures, and increases the risk of death. The nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) inflammasome is an intracellular multiprotein complex that regulates the maturation and secretion of Caspase-1 dependent proinflammatory cytokines interleukin (IL)-1β and IL-18, mediates inflammation, and induces pyroptosis. The chronic inflammatory microenvironment induced by aging or estrogen deficiency activates the NLRP3 inflammasome, promotes inflammatory factor production, and enhances the inflammatory response. We summarize the related research and demonstrate that the NLRP3 inflammasome plays a vital role in the pathogenesis of osteoporosis by affecting the differentiation of osteoblasts and osteoclasts. IL-1β and IL-18 can accelerate osteoclast differentiation by expanding inflammatory response, and can also inhibit the expression of osteogenic related proteins or transcription factors. In vivo and in vitro experiments showed that the overexpression of NLRP3 protein was closely related to aggravated bone resorption and osteogenesis deficiency. In addition, abnormal activation of NLRP3 inflammasome can not only produce inflammation, but also lead to pyroptosis and dysfunction of osteoblasts by upregulating the expression of Caspase-1 and gasdermin D (GSDMD). In conclusion, NLRP3 inflammasome overall not only accelerates bone resorption, but also inhibits bone formation, thus increasing the risk of osteoporosis. Thus, this review highlights the recent studies on the function of NLRP3 inflammasome in osteoporosis, provides information on new strategies for managing osteoporosis, and investigates the ideal therapeutic target to treat osteoporosis.

Keywords: NLRP3; inflammasome; osteoblasts; osteoclasts; osteoporosis.

Figure 1

Structure of nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) inflammasome. NLRP3 inflammasome comprises a leucine-rich repeat (LRR) domain, an N-terminal Pyrin domain (PYD), and a central adenosine triphosphatase (ATPase) domain known as NACHT. Caspase-1 comprises CARD and two subunits, p10 and p20. NLRP3 and ASC interact with their respective PYDs. ASC and Caspase-1 interact with their respective CARDs.

Figure 2

Activation mechanism of nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) inflammasome. NLRP3 is activated by two signals when it senses the stimulation of aging or estrogen deficiency through toll like receptors (TLRs). The first priming process (Signal 1) is the expression of NLRP3 and inflammatory factors under the action of the NF-κB transcription factor. Next, it induces uniform downstream host-derived cellular events, including K⁺ efflux, Ca²⁺ efflux, reactive oxygen species (ROS) generation, and lysosomal damage. ASC is an adaptor molecule responsible for connecting NLRP3 and caspase-1 precursors, and then recruits the precursor caspase-1 into an activated form (Signal 2). Activated caspase-1 cleaves the precursors of IL-1β and IL-18 into mature forms and causing inflammation.

Figure 3

IL-1beta contributes to bone resorption. IL-1β inhibits osteogenic differentiation by inhibiting the BMP/Smad pathway and osteogenic markers including RUNX2, OCN and ALP. IL-1β binds with IL-1R on T cells or B cells and induces the expression of RANKL on osteoblasts and then promotes activated osteoclasts via a RANKL-RANK independent mechanism.

Figure 4

Hypothesized participation of nucleotide-binding oligomerization domain-like-receptor family pyrin domain-containing 3 (NLRP3) inflammasome in the pathogenesis of osteoporosis.